DESCRIPTION: The endocannabinoid (EC) system plays a critical role in the pathogenesis of neuroinflammatory and neurodegenerative disorders, including regulating pro-inflammatory cytokines, endothelial activation, and oxidative stress. Over the past decade, preclinical studies have indicated that the anti-inflammatory and neuroprotective properties of the EC system, including activation of the EC CB2 receptor, may have therapeutic utility in reducing HIV-induced damage to the central nervous system (CNS) and preventing the development of HIV-associated neurocognitive disorders (HAND). In contrast, exogenous cannabis use is reported to induce neurocognitive and functional impairment after chronic exposure. Although the neurobiological mechanisms underlying these effects remain speculative, cannabis exposure reduces EC ligand and receptor expression in both humans and mice, suggesting that disruption of the EC system may play a critical role in the detrimental effects of this drug. While recent work indicates that exogenous cannabis can block upregulated EC activity in schizophrenia patients, the individual and combined effects of HIV and cannabis use on the EC system have not been characterized, representing a fundamental gap in our knowledge. Thus, this application will examine the relationship between cannabis use, EC function, and mechanisms of HIV-related pathogenesis implicated in the development of HAND. We will quantify cerebrospinal fluid (CSF) and plasma levels of the two primary endocannabinoid ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in HIV- and HIV+ participants (n of 50 per group) with no cannabis use (d 5 times over lifetime), light cannabis use (1-4 times per month in past year), and heavy cannabis use (>10 times per month in past year and meeting criteria for lifetime cannabis abuse or dependence). To assess potential mechanisms of HIV-EC interaction, we will also examine expression of the CB2 receptor in monocytes and T- cells, as well as the EC ligand deactivation enzymes fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MAGL). We propose that EC ligand and receptor expression will be elevated in cannabis-naive HIV+ participants as a compensatory protective mechanism, but decline in participants with heavy cannabis use. We will also test the hypothesis that higher levels of AEA, 2-AG and CB2 expression will be associated with lower levels of neuroinflammatory markers, endothelial activation, and oxidative stress. Finally, we propose that heavy cannabis use will impair neurocognitive performance compared to no cannabis use in HIV+ participants, but higher EC activity will be associated with better neurocognitive function. In summary, this approach will allow us to elucidate several key issues, including the interaction between cannabis and the EC system, potential mechanisms that underlie these effects (lower CB2 receptor and increased FAAH expression), the assessment of EC effects on multiple biological processes implicated in HIV-mediated CNS deterioration, and the relationship between EC activity and neurocognitive performance.